eIF4F controls ERK MAPK signaling in melanomas with <i>BRAF</i> and <i>NRAS</i> mutations

The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a function of eIF4F in the negative regulation of the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for controlling ERK signaling intensity in treatment-naïve melanoma cells harboring <i>BRAF</i> or <i>NRAS</i> mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small-molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with <i>BRAF</i> and <i>NRAS</i> activating mutations.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2024-10-22
DOI
https://doi.org/10.1073/pnas.2321305121
Citations
7
Primary Topic
Melanoma and MAPK Pathways
Type
article
Field-Weighted Citation Impact
1.64

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article

eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations

Barbora Valčíková, Pavel Krejčı́, Shannon Lee, Walter Kölch et al.
7 citations
Proceedings of the National Academy of Sciences
Melanoma and MAPK Pathways
1.64
article

eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations

Barbora Valčíková, Pavel Krejčı́, Shannon Lee, Walter Kölch, Alex von Kriegsheim, Jens Rauch, Ondřej Vacek, Stjepan Uldrijan, Ráchel Víchová, Natália Vadovičová, Katarína Smolková, Karel Souček, Zdeněk Andrysík, Anna Dorotikova, Magdalena Zacpalova
article en
7 citations

Abstract

The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a function of eIF4F in the negative regulation of the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for controlling ERK signaling intensity in treatment-naïve melanoma cells harboring <i>BRAF</i> or <i>NRAS</i> mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small-molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with <i>BRAF</i> and <i>NRAS</i> activating mutations.

Proceedings of the National Academy of SciencesVol. 121(44)
University College Dublin (IE), Masaryk University (CZ), Edinburgh Cancer Research (GB), Czech Academy of Sciences, Institute of Biophysics (CZ), Czech Academy of Sciences, Institute of Animal Physiology and Genetics (CZ), University Hospital Brno (CZ), St. Anne's University Hospital Brno (CZ), University of Colorado Anschutz Medical Campus (US)
Wellcome Trust, European Commission, Science Foundation Ireland, Grantová Agentura České Republiky, Central European Institute of Technology, Masarykova Univerzita, European Regional Development Fund
Good health and well-being
Openalex Percentile: Top 16%
Melanoma and MAPK Pathways
1.64
DOIOpen Access PDFOpenAlex
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